Anneline S J M te Riele1, Cynthia A James2, Judith A Groeneweg3, Abhishek C Sawant2, Kai Kammers4, Brittney Murray2, Crystal Tichnell2, Jeroen F van der Heijden5, Daniel P Judge2, Dennis Dooijes6, J Peter van Tintelen7, Richard N W Hauer3, Hugh Calkins2, Harikrishna Tandri8. 1. Department of Medicine, Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA Department of Medicine, Division of Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands. 2. Department of Medicine, Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. 3. Department of Medicine, Division of Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands ICIN-Netherlands Heart Institute, Utrecht, The Netherlands. 4. Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA. 5. Department of Medicine, Division of Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands. 6. Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands. 7. ICIN-Netherlands Heart Institute, Utrecht, The Netherlands Department of Clinical Genetics, Academic Medical Center Amsterdam, Amsterdam, The Netherlands. 8. Department of Medicine, Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA htandri1@jhmi.edu.
Abstract
AIMS: A combination of variable expression, age-related penetrance, and unpredictable arrhythmic events complicates management of relatives of arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) patients. We aimed to (i) determine predictors of ARVD/C diagnosis and (ii) optimize arrhythmic risk stratification among first-degree relatives of ARVD/C patients. METHODS AND RESULTS: Detailed phenotypic and outcome data of 274 first-degree relatives (46% male; 36.5 ± 18.9 years) of 138 ARVD/C probands were obtained. Ninety-six (35%) relatives were diagnosed with ARVD/C according to 2010 Task Force Criteria (TFC). Siblings had a three-fold-increased risk of ARVD/C diagnosis compared with parents and children (odds ratio 3.11, P < 0.001). Multivariable logistic regression identified symptoms (P < 0.001), being a sibling (P < 0.001), the presence of a pathogenic mutation (P < 0.001), and female sex (P = 0.010) as predictors of ARVD/C diagnosis. During 6.7 ± 3.8 years of follow-up, 21 (8%) relatives experienced a sustained ventricular arrhythmia (cycle length 271 ± 48 ms). While being a sibling was a predictor of ARVD/C diagnosis, neither relatedness to the proband (P = 0.185) nor malignant family history (P = 0.347) was significantly associated with arrhythmic events. Meeting TFC independent of family history criteria had higher prognostic value for arrhythmic events than conventional 2010 TFC, which include family history [area under the receiver operating characteristic curve 0.95 (95% CI 0.93-0.97) vs. 0.85 (95% CI 0.82-0.88), P < 0.001]. CONCLUSION: One-third of first-degree relatives develop manifest ARVD/C. Siblings have highest risk of disease, even after correcting for age and sex. Fulfilment of TFC independent of family history is superior to conventional TFC for arrhythmic risk stratification of relatives. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: A combination of variable expression, age-related penetrance, and unpredictable arrhythmic events complicates management of relatives of arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) patients. We aimed to (i) determine predictors of ARVD/C diagnosis and (ii) optimize arrhythmic risk stratification among first-degree relatives of ARVD/C patients. METHODS AND RESULTS: Detailed phenotypic and outcome data of 274 first-degree relatives (46% male; 36.5 ± 18.9 years) of 138 ARVD/C probands were obtained. Ninety-six (35%) relatives were diagnosed with ARVD/C according to 2010 Task Force Criteria (TFC). Siblings had a three-fold-increased risk of ARVD/C diagnosis compared with parents and children (odds ratio 3.11, P < 0.001). Multivariable logistic regression identified symptoms (P < 0.001), being a sibling (P < 0.001), the presence of a pathogenic mutation (P < 0.001), and female sex (P = 0.010) as predictors of ARVD/C diagnosis. During 6.7 ± 3.8 years of follow-up, 21 (8%) relatives experienced a sustained ventricular arrhythmia (cycle length 271 ± 48 ms). While being a sibling was a predictor of ARVD/C diagnosis, neither relatedness to the proband (P = 0.185) nor malignant family history (P = 0.347) was significantly associated with arrhythmic events. Meeting TFC independent of family history criteria had higher prognostic value for arrhythmic events than conventional 2010 TFC, which include family history [area under the receiver operating characteristic curve 0.95 (95% CI 0.93-0.97) vs. 0.85 (95% CI 0.82-0.88), P < 0.001]. CONCLUSION: One-third of first-degree relatives develop manifest ARVD/C. Siblings have highest risk of disease, even after correcting for age and sex. Fulfilment of TFC independent of family history is superior to conventional TFC for arrhythmic risk stratification of relatives. Published on behalf of the European Society of Cardiology. All rights reserved.
Authors: Eric D Carruth; Wilson Young; Dominik Beer; Cynthia A James; Hugh Calkins; Linyuan Jing; Sushravya Raghunath; Dustin N Hartzel; Joseph B Leader; H Lester Kirchner; Diane T Smelser; David J Carey; Melissa A Kelly; Amy C Sturm; Amro Alsaid; Brandon K Fornwalt; Christopher M Haggerty Journal: Circ Genom Precis Med Date: 2019-10-22
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